Adenylate analogs as potent anti-herpes virus agents

ABSTRACT

Novel adenylate analogs having the following formula are synthesized in the present invention, which are found active against herpes simplex viruses: ##STR1## wherein R 1  is hydroxyl, C 1  -C 4  alkoxy, an amino ester radical of --NHR 3  COOR 4 , wherein R 3  is a bivalent C 1  -C 4  saturated hydrocarbon and R 4  is C 1  -C 4  alkyl; and R 2  is hydroxyl, --O +  NH 4  or ##STR2##

FIELD OF THE INVENTION

The present invention is related generally to synthesis of noveladenylate analogs and their pharmaceutical use, and more particularly tosynthesis of novel adenylate analogs which are active against herpessimplex viruses (HSV).

BACKGROUND OF THE INVENTION

Acyclic adenosine VI Schaeffer, H. J., et al. Novel Substrate ofAdenosine Deaminase. J. Med. Chem. 1971, 14, 367-369! and9-(β-D-arabinofuranosyl)adenine 37 (arabinoside, Ara-A) Shannon, W. M.In Adenine Arabinoside, an Antiviral Agent, Pavan-Langston, D.;Buchanan. R. A.; Alford, C. A., Eds. Raven Press, New York, 1975, pp1-44! can inhibit viral replication. However, Ara-A is also known beingable to be converted in vivo to hypoxanthine (Ara-Hx) via deamination byadenosine deaminase, which adversely affects the activity of Ara-A ininhibition of viral replication. Ara-A is also potent in treating apatient having acute type B hepatitis. In addition to the deamination,the potency of Ara-A is also reduced due to its poor lipophilicity.##STR3##

SUMMARY OF THE INVENTION

The present invention discloses a novel adenylate analog having thefollowing formula: ##STR4## wherein R¹ is hydroxyl, C₁ -C₄ alkoxy, anamino ester radical of --NHR³ COOR⁴, wherein R³ is a bivalent C₁ -C₄saturated hydrocarbon and R⁴ is C₁ -C₄ alkyl; and

R² is hydroxyl, --O⁺ NH₄ or ##STR5## or pharmaceutically acceptablesalts thereof.

Preferably, R¹ of the adenylate analog of formula I is methylL-alaninate (L)-NHCHCH₃ CO₂ CH₃ !.

Preferably, R² of the adenylate analog of formula I is ##STR6##

The present invention also provides a pharmaceutical composition for thetreatment of a human infected by a herpes simplex virus (HSV) comprisinga therapeutically effective amount of the adenylate analog of theformula I or a pharmaceutically acceptable salt thereof, as an activeingredient, in admixture with a pharmaceutically acceptable carrier ordiluent for the active ingredient.

The present invention further provides a method for the treatment of ahuman infected by a herpes simplex virus (HSV) comprising administeringa therapeutically effective amount of the adenylate analog of theformula I to a human infected by a herpes simplex virus (HSV).

The adenylate analog of the formula I synthesized in accordance with thepresent invention is found potent in inhibiting cytopathogenicity ofherpes simplex type 1 virus (HSV-1), herpes simplex type 2 virus (HSV-2)and varicella-zoster virus (VZV) in Hela cell culture, and having a lowcellular toxicity.

In the preferred embodiments of the present invention, the followingadenylate analogs 12, 13, 40 and 42 were synthesized. Compounds 12 and13 of the adenylate analogs are nucleotide analogs, and the compounds 40and 42 are dinucleotide analogs. ##STR7## wherein Me is methyl and Et isethyl (these abbreviations also apply in the following text).

Among the adenylate analogs synthesized in the present invention, thedinucleotide analogs are believed to have better antiherpes virusactivity compared to the nucleotide analogs. The former are synthesizedaccording to a design of combination therapy, wherein acyclic adenosineVI and Ara-A 37 are connected with a phosphonate structure. Moreover,the dinucleotide analogs show a superior lipophilicity and watersolubility, when R¹ in the formula I is the amino ester radical, whichenhance the efficiency of the transport of the adenylate analogs throughthe cell membranes, and thus increases its antiherpes virus activity andits ability to inhibit the deamination caused by adenosine deaminase.

Synthesis of Acyclic Nucleoside Phosphonate 13 (Scheme 1)

We carried out the Arbuzov reaction Holy, A. Synthesis of5'-Deoxyuridine 5'-Phosphonic Acid. Tetrahedron Lett. 1967, 881-884! bytreatment of acyclonucleoside 7 with triethyl phosphite to produce thedesired diethyl phosphonate 11. Reaction of 11 with NH₃ in MeOH gavemono-ammonium salt 12 in 40% yield. We then treated 12 with Me₃ SiBr inDMF to provide a 45% yield of the desired phosphonate 13, which mayexist in its zwitterionic form.

Syntheses of Phosphonate 40 as well as Phosphonoamidate 42 (Scheme 7)

The dinucleotide phosphonate 40 was readily obtained in three steps fromarabinoadenosine 37, which was first silylated with (t-Bu)Me₂ SiCl inthe presence of AgNO₃, pyridine, and THF (see Scheme 7). We thencondensed the resultant 2',5'-disilyl ether 38 (97%) with phosphonicacid 13 by using trichloromethanesulfonyl chloride in collidine and THFto afford nucleotide phosphonate 39 in 55% yield. Desilylation of 39with (n-Bu)₄ NF at 25° C. gave the target molecule 40 in 78% yield.

We condensed nucleotide phosphonate 39 with methyl L-alaninate by using(triisopropyl)benzenesulfonyl chloride to give a diastereoisomericmixture of phosphonoamidates 41 (1:1) in 97% yield. Compounds 41 showedtwo close signals at δ38.71 and 38.80 ppm in its ³¹ P NMR spectrum,resulting from the phosphonoamidate chiral center. Desilylation of 41with (n-Bu)₄ NF afforded the target phosphonoamidate 42 in 90% yield.##STR8##

Reagents: (a) (EtO)₃ P, Δ; (b) NH₃, MeOH; (c) Me₃ SiBr, DMF ##STR9##

Reagents: (a) t-BuMe₂ SiCl, AgNO₃, pyridine, THF; (b) CCl₃ SO₂ Cl,collidine, THF; (c) (n-Bu)₄ NF, THF; (d)2,4,6-triisopropylbenzenesulfonyl chloride, methyl L-alaninate,pyridine.

The invention will be further illustrated by the following exampleswhich are only meant to illustrate the invention, but not to limit it.The reaction routes for synthesizing the title compounds of thePreparation Examples 1-3 and 4-7 are shown in the Schemes 1 and 7,respectively.

PREPARATION EXAMPLE 1 Diethyl 2-(6-Methoxypurin-9-yl)methoxy!ethyl!phosphonate (11)

A mixture of 7 (2.87 g, 10.0 mmol) and triethyl phosphite (8.30 g, 50.0mmol) was heated at 150° C. for 24 h. Ether (300 mL) was added to thesolution at room temperature and the resultant precipitate was filtered.Crystallization from a mixture of MeOH and Et₂ O (1:4) gave 11 (1.01 g)in 30% yield: mp 140°-141° C.; TLC Rf 0.17 (AcOEt/MeOH=4:1); UV λ_(max)(EtOH): 249 nm (ε12 250); ¹ H NMR (CDCl₃): δ1.10-1.54 (m, 8 H, 2×CH₃+CH₂ P), 3.39-4.30 (m, 6 H, 2×CH₂ OP+CH₂ O), 4.15 (s, 3 H, OCH₃), 5.61(s, 2 H, OCH₂ N), 8.12, 8.41 (2 s, 2 H, HC(2)+HC(8)). Anal. (C₁₃ H₂₁ N₄O₅ P) C, H, N.

PREPARATION EXAMPLE 2 Ammonium Ethyl 2-(Adenin-9-yl)methoxy!ethyl!phosphonate (12)

To a solution of 11 (3.44 g, 10.0 mmol) in MeOH (40 mL) was added asaturated methanolic NH₃ solution (100 mL). The solution was heated in asealed flask at 100° C. for 30 h. The solvent was evaporated and theresidue was crystallized from EtOH to give 12 (1.20 g) in 40% yield: mp190°-193° C.; TLC Rf 0.37 (AcOEt/MeOH=1:1); UV λ_(max) (EtOH): 260 nm(ε14 000); ¹ H NMR (DMSO-d₆ /D₂ O): δ1.20-1.56 (m, 5 H, CH₃ +CH₂ P),3.40-4.10 (m, 2 H, CH₂ OP), 4.30 (m, 2 H, CH₂ O), 5.60 (s, 2 H, OCH₂ N),7.80, 8.12 (2 s, 2 H, HC(2) +HC(8)). Anal. (C₁₀ H₁₉ N₆ O₄ P) C, H, N.

PREPARATION EXAMPLE 3 2- (Adenin-9-yl)methoxy!ethylphosphonic Acid (13)

To a solution of 12 (0.32 g, 1.0 mmol) in DMF (7.0 mL) was added Me₃SiBr (1.07 g, 7.01 mmol). After the solution was stirred at 40° C. for 6h, a mixture of MeOH and H₂ O(5:1, 20 mL) was added and the solventswere evaporated. The crude residue was purified by use of columnchromatography (resin XAD-4, H₂ O) to afford 13 (0.12 g, 45%): mp 296°C. (dec.); TLC Rf 0.32 (MeOH); UV λ_(max) (EtOH): 259 nm (ε13 700); ¹ HNMR(DMSO-d₆ /D₂ O): δ1.49 (m, 2 H, CH₂ P), 3.80 (m, 2 H, CH₂ O), 5.55(s, 2 H, OCH₂ N), 7.90, 8.19 (2 s, 2 H, HC(2)+HC(8)). Anal. (C₈ H₁₂ N₅O₄ P) C, H, N.

PREPARATION EXAMPLE 4 9-2',5'-Bis-O-(tert-butyldimethylsilyl)-β-D-arabinofuranosyl!adenine-3'-2-(adenin-9-ylmethoxy)ethyl!phosphonate! (39)

Collidine (0.61 g, 5.0 mmol) was added to a solution of THF (2.0 mL)containing 13 (0.27 g, 0.99 mmol) at -10° C. To this solution was addedCCl₃ SO₂ Cl (0.22 g, 1.0 mmol) in THF (0.50 mL) dropwise. After 38 (0.50g, 1.0 mmol) in THF (2.0 mL) was added into the mixture, it was stirredat 25° C. for 10 h. The solvents were removed and the residue wasdissolved in AcOEt (20 mL) and washed with H₂ O (20 mL). The organiclayer was concentrated and the residue was purified by use ofpreparative TLC with a mixture of CHCl₃ and MeOH (6:1) as the eluant.The band at Rf ca. 0.50 was eluted with AcOEt to afford 39 (0.41 g) in55% yield: mp 129°-131° C.; TLC Rf 0.50 (CHCl₃ /MeOH=6:1); UV λ_(max)(EtOH): 259 nm (ε17 500); ¹ H NMR(DMSO-d₆ /D₂ O): δ0.15 (br s, 12 H,2×(CH₃)₂ Si), 0.90, 1.15 (2 s, 18 H, 2×(CH₃)₃ C), 1.68 (m, 2 H, CH₂ P),3.81-4.26 (m, 4 H, CH₂ O+H₂ C(5')), 4.31-4.76 (m, 3 H,HC(2')+HC(3')+HC(4')), 5.61 (s, 2 H, OCH₂ N), 6.57 (d, J=4.8 Hz, 1 H,HC(1')), 8.01, 8.12, 8.52, 8.71 (4 s, 4 H, 2×HC(2)+2×HC(8)); ³¹ P NMR(DMSO-d₆): δ29.20. Anal. (C₃₀ H₅₁ N₁₀ O₇ PSi₂) C, H, N.

PREPARATION EXAMPLE 5 9-(β-D-Arabinofuranosyl)adenine-3'-2-(Adenin-9-ylmethoxy)ethyl!phosphonate! (40)

To a solution of 39 (0.37 g, 0.49 mmol) in THF (3.0 mL) was added(n-Bu)₄ NF (1.0M solution in THF, 0.31 g, 1.2 mmol). Acetic acid (0.50mL) was added to the mixture after it was stirred at 25° C. for 30 min.The solvents were removed and the residue was purified by use of Whatman3-mm paper with a mixture of i-PrOH, NH₄ OH, and H₂ O (9:1:2) as theeluant. The band at Rf ca. 0.42 was eluted with H₂ O and collected bylyophilization to give 40 (0.20 g) in 78% yield: mp>250° C. (dec.); UVλ_(max) (EtOH): 258 nm (ε18 000); ¹ H NMR (DMSO-d₆ /D₂ O): δ1.59 (m, 2H, CH₂ P), 3.78-4.12 (m, 4 H, CH₂ O+H₂ C(5')), 4.28-4.75 (m, 3 H,HC(2')+HC(3')+HC(4')), 5.59 (s, 2 H, OCH₂ N), 6.50 (d, J=4.3 Hz, 1 H,HC(1')),7.99, 8.18, 8.60, 8.80(4s, 4H, 2×HC(2)+2×HC(8)); ³¹ P NMR(DMSO-d₆): δ29.25. Anal. (C₁₈ H₂₃ N₁₀ O₇ P) C, H, N.

PREPARATION EXAMPLE 6 9-2',5'-Bis-O-(tert-butyldimethylsilyl)-β-D-arabinofuranosyl!adenine-3'-(Methoxyalaninyl) 2-(adenin-9-ylmethoxy!ethyl!phosphonates!(Diastereoisomeric Mixture; 41)

To a solution of 39 (0.75 g, 1.0 mmol) in pyridine (6.0 mL) was added2,4,6-(triisopropyl)benzenesulfonyl chloride (0.54 g, 1.8 mmol), Afterthe mixture was stirred at 25° C. for 13 h, methyl L-alaninate (0.26 g2.5 mmol) in pyridine (2.0 mL) was added and the mixture was stirred at25° C. for 4 h. The solvent was removed and the residue was dissolved inAcOEt (30 mL). The organic layer was washed with H₂ O (2×30 mL), dried,and concentrated. The residue was purified by use of preparative TLCwith a mixture of CHCl₃ and MeOH (6:1) as the eluant. The band at Rf ca.0.69 was eluted with a mixture of AcOEt and CHCl₃ (2:1) to afford 41(0.81 g) in 97% yield: TLC Rf 0.69 (CHCl₃ /MeOH=6:1); UV λ_(max) (EtOH):260 nm (ε17 800); ¹ H NMR (CDCl₃ /DMSO-d₆ /D₂ O): δ0.16, 0.18 (2 s, 12H, 2×(CH₃)₂ Si), 0.83, 1.06 (2 s, 18 H, 2×(CH₃)₃ C), 1.42 (d, J=5.8 Hz,3 H, CH₃), 1.69 (m, 2 H, CH₂ P), 3.68-4.25 (m, 8 H, CH₃ O+CH₂ O+CH+H₂C(5')), 4.33-4.78 (m, 3 H, HC(2')+HC(3') +HC(4')), 5.62 (s, 2 H, OCH₂N), 6.56 (d, J=4.9 Hz, 1 H, HC(1')), 8.06, 8.13, 8.54, 8.73 (4 s, 4 H,2×HC(2)+2×HC(8)); ³¹ P NMR (DMSO-d₆) δ38.71, 38.80. Anal. (C₃₄ H₅₈ N₁₁O₈ PSi₂) C, H, N.

PREPARATION EXAMPLE 7 9-(β-D-Arabinofuranosyl)adenine-3'-(Methoxyalaninyl) 2-(adenin-9-ylmethoxy)ethyl!phosphonates!(Diastereoisomeric Mixture; 42)

Compound 42 was obtained from 41 (1.20 g, 1.43 mmol) by following theprocedure for preparation of 40 from 39. The crude material was purifiedby use of TLC plates and eluted with a mixture of CHCl₃ and MeOH (6:1).The desired product 42 (0.78 g) was isolated in 90% yield: TLC Rf 0.16(CHCl₃ /MeOH=6:1); paper chromatography, Rf 0.62 (i-PrOH/NH₄ OH/H₂O=9:1:2); UV λ_(max) (EtOH): 259 nm (ε18 760); ¹ H NMR (DMSO-d₆ /D₂ O):δ1.40 (d, J=5.9 Hz, 3 H, CH₃), 1.66 (m, 2 H, CH₂ P), 3.70-4.10 (m, 8 H,CH₃ O+CH₂ O+CH+H₂ C(5')), 4.32-4.76 (m, 3 H, HC(2')+HC(3')+HC(4')), 5.59(s, 2 H, OCH₂ N), 6.51 (d,J=4.3 Hz, 1 H, HC(1')), 8.05, 8.14, 8.56, 8.76(4 s, 4 H, 2×HC(2)+2×HC(8)); ³¹ P NMR(DMSO-d₆): 38.70, 38.82. Anal. (C₂₂H₃₀ N₁₁ O₈ P) C, H, N.

EXAMPLE 1 Kinetic Studies of Competitive Inhibition of AdenosineDeaminase by Nucleoside and Nucleotide Analogs

By following an established procedure Ogilvie, K. K.; Nguyen-Ba, N.;Gillen, M. F.; Radatus, B. K.; Cheriyan, U. O.; Hanna, H. R.; Smith, K.O.; Galloway, K. S. Synthesis of A Purine Acyclonucleoside Series HavingPronounced Antiviral Activity. The Glyceropurines. Can. J. Chem. 1984,62, 241-252.!, we determined the rates of deamination of VI, 13, 37, 40,and 42 in the presence of calf mucosal adenosine deaminase (EC 3.5.4.4)in buffer solutions. Inhibition studies on these compounds were carriedout on the basis of the Kaplan method (Moosavi-Movahedi, A. A.; Rahmani,Y.; Hakimelahi G. H., Thermodynamic and Kinetic Studies of CompetitiveInhibition of Adenosine Deaminase by Ring Open Analogues of AdnineNucleotides. Int. J. Biol. Micromol. 1993, 15,125-129). The results areshown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Substrate Activities and Inhibitory Properties against Adenosine              Deaminase                                                                     substrate K.sub.m (μM)                                                                            rel V.sub.max                                                                           K.sub.I (μM)                              ______________________________________                                        13        247.5        1.49 × 10.sup.-6                                                                  18.2                                         40        166.2        7.64 × 10.sup.-2                                 42        .sup.a       .sup.a                                                 VI        138.0        1.52 × 10.sup.-2                                                                  142.5                                        37        45.3         1                                                      ______________________________________                                         .sup.a No reaction at 1500 μM.                                        

We found that acyclonucleoside VI and acyclic nucleoside phosphonate 13were adenosine deaminase substrates. The V_(max) of 13 was, however,˜10⁻⁴ times less than that of VI. Compounds VI and 13 showed competitiveinhibition of adenosine deaminase when Ara-A 37 was used as a substrate.Nevertheless, phosphonate 13 acted more efficiently thanacyclonucleoside VI as an inhibitor of adenosine deaminase. Nucleotideanalog 40 was also a substrate of adenosine deaminase, but its V_(max)was 92% less than that of Ara-A 37. The slow rate of deamination ofcompound 40 towards adenosine deaminase may reflect the inhibitoryaction of the acyclic nucleotide moiety therein at the active site ofthe enzyme. Subsequently, by assaying against calf mucosal adenosinedeaminase in vitro, we found that phosphonoamidate 42 completelyresisted deamination.

EXAMPLE 2 Determination of Solubility and Partition Coefficients(Lipophilicity) of Adenylate Analogs

Determination of Solubility

Each compound (70 mg) listed in Table 2 was agitated in a 25-mLvolumetric flask with phosphate buffer (0.10M, 5.0 mL) for 20 h. Thissolution was filtered from undissolved solid through a sintered glassfunnel (4.0-5.5 mesh ASTM) and the concentration of the solution wasdetermined by UV absorbance (Table 2).

Determination of Partition Coefficients (Lipophilicity)

A solution of each compound (10 mL) in Table 2 in phosphate buffer(0.10M) possessing an UV absorbance of 2.2-3.3 at 258-265 nm was shakenwith 1-pentanol (10 mL) in a separatory funnel for 1.5 h. The layerswere separated, and their concentrations were determined by an UVspectrophotometer. The partition coefficient was calculated as P=S!_(1-pentanol) / S!H₂ O (Table 2).

                  TABLE 2                                                         ______________________________________                                        Solubility in H.sub.2 O and Lipophilicity of Nucleoside and Nucleotide        Analogs                                                                       compound    solubility in H.sub.2 O (mg/mL)                                                               log P.sup.a                                       ______________________________________                                        13          13.64           0.07                                              40          2.46            -0.68                                             42          8.25            0.87                                              VI          1.95            0.98                                              37          0.40            -0.47                                             ______________________________________                                         .sup.a Partition coefficients were calculated as follows:                     P =  Substrate!.sub.1pentanol / Substrate!.sub.H.sbsb.2.sub.O.           

We found from Table 2 that compounds 13, 40 and 42 synthesized inaccordance with the present invention had partition coefficients rangingfrom 0.1 to 10, and had a higher water solubility.

EXAMPLE 3 Anti-Herpes and Anticellular Activities of Nucleoside andNucleotide Analogs in Tissue Culture

We tested the synthesized compounds for their inhibition ofcytopathogenicity of herpes simplex type 1 virus (HSV-1), herpes simplextype 2 virus (HSV-2), and varicella-zoster virus (VZV) in Hela cellculture. These compounds include VI, 12, 13, 40, 42, a mixture of VI and13 (1:1), ara-A 37, and a mixture of 13 and 37 (1:1). Toxicity of thesecompounds was evaluated by their ability to cause morphological changesin cells at different concentrations. The minimum inhibitoryconcentrations (IC₅₀), measured by use of the linear regression method,are summarized in Table 3.

                  TABLE 3                                                         ______________________________________                                        Anti-Herpes and Anticellular Activities of Nucleoside and Nucleotide          Analogs in Tissue Culture                                                               IC.sub.50 (μg/ml).sup.a                                                      HSV-1   HSV-2     VZV                                             compounds   (KOS)   (G)       (YS) Hela cell.sup.b                            ______________________________________                                        12          11.26   13.80     25.00                                                                              175.60                                     13          3.98    5.86      16.00                                                                              215.00                                     40          8.97    16.29     .sup.c                                                                             346.07                                     42          0.38    0.88      4.82 215.48                                     VI          4.43    8.26      6.50 265.70                                     37          10.80   .sup.c    .sup.c                                                                             98.85                                      13 + VI (1:1)                                                                             0.15    0.38      0.18 235.25                                     13 + 37 (1:1)                                                                             0.67    1.25      2.86 167.82                                     ______________________________________                                         .sup.a Inhibitory concentrations (IC.sub.50) represent the average of         triplicate determinations;                                                    .sup.b Concentration of the compound required to cause microsopically         visible change or disruption in about 50% of the cell sheet; and              .sup.c Not active up to 128 μg/mL.                                    

It can be seen from Table 3 that compounds 12, 13, 40 and 42 of thepresent invention all exhibit antiviral activity against herpes simplextype 1 virus (HSV-1), herpes simplex type 2 virus (HSV-2) andvaricella-zoster virus (VZV) in Hela cell culture with the exceptionthat compound 40 is not active against VZV. Moreover, compounds 12, 13,40 and 42 synthezied in the present invention have a lower cellulartoxicity in comparison with that of Ara-A 37 compound.

Adenosine deaminase can form a complex with acyclonucleoside VI andarabinoside 37 (Table 1), thus their antiviral activity is decreased.Compound 13 of the present invention inhibits adenosine deaminase (Table1 ). As a result of this inhibition, a synergistic effect on theantiviral activity of VI and Ara-A 37 by mixing with compound 13 waspredicted and was observed (Table 3).

The ability of a drug to penetrate a membrane and to exhibit biologicalactivity is correlated to its lipophilicity (Tables 2 and 3). Thephosphonoamidate derivative 42 as a lipophilic pro-drug, which displayedsuperior antiviral activity (Table 3). The activity increment of 42 overacyclic nucleoside phosphonate 13, Ara-A 37, and dinucleotidephosphonate 40 may be due to a combination of increased lipophilicityand resistance to adenosine deaminase (Tables 1-3). We hypothesize that,as a masked membrane-soluble form of the bioactive nucleotide analog 40,phosphonoamidate 42 may act as a proteinase substrate. With the aid ofphosphodiesterases, the biologically active compounds 13 and 37 werethen liberated as potential drugs, and were effective against infectedcells (Table 3).

The embodiments of the present invention described above are to beregarded in all respects as being merely illustrative and notrestrictive. Accordingly, the present invention may be embodied in otherspecific forms without deviating from the spirit thereof. The presentinvention is therefore to be limited only by the scopes of the followingappended claims.

What is claimed is:
 1. An adenylate analog having the following formula:##STR10## wherein R¹ is hydroxyl, C₁ -C₄ alkoxy, an amino ester radicalof --NH--R³ --COOR⁴,wherein R³ is a bivalent C₁ -C₄ saturatedhydrocarbon and R⁴ is C₁ --C₄ alkyl; and R² is hydroxyl, --O⁻ NH₄ ⁺ or##STR11## or a pharmaceutically acceptable salt thereof.
 2. Theadenylate analog as defined in claim 1, wherein R² is: ##STR12##
 3. Theadenylate analog as defined in claim 1, wherein R¹ is methyl L-alaninate((L)-NHCHCH₃ CO₂ CH₃).
 4. The adenylate analog as defined in claim 2,wherein R¹ is methyl L-alaninate ((L)-NHCHCH₃ CO₂ CH₃).
 5. Apharmaceutical composition comprising a therapeutically effective amountof the adenylate analog as defined in claim 1 or a pharmaceuticallyacceptable salt therof, as an active ingredient, in admixture with apharmaceutically acceptable carrier or diluent.
 6. The pharmaceuticalcomposition as defined in claim 5, wherein R² is: ##STR13##
 7. Thepharmaceutical composition as defined in claim 5, wherein R¹ is methylL-alaninate ((L)-NHCHCH₃ CO₂ CH₃).
 8. The pharmaceutical composition asdefined in claim 6, wherein R¹ is methyl L-alaninate ((L)-NHCHCH₃ CO₂CH₃).
 9. A method for the treatment of a human infected by a herpessimplex virus comprising administering a therapeutically effectiveamount of the adenylate analog as defined in claim 1 to a human infectedby a herpes simplex virus.
 10. The method as defined in claim 9, whereinR² is: ##STR14##
 11. The method as defined in claim 10, wherein R¹ ismethyl L-alaninate ((L)-NHCHCH₃ CO₂ CH₃).
 12. The method as defined inclaim 11, wherein R¹ is methyl L-alaninate ((L)-NHCHCH₃ CO₂ CH₃).